Can a relative overdose of benzodiazepines be safely antagonized?
Flumazenil is an intravenously administered competi-tive benzodiazepine receptor antagonist at specific benzo-diazepine binding sites in the central nervous system. It can be judiciously titrated to obtain the desired degree of benzodiazepine reversal as evidenced by patient arousal. Previously, two drugs were available for this purpose. Physostigmine, a nonspecific centrally acting arousal agent, appears to antagonize the central nervous system depressant effects of both volatile anesthetic agents and benzodiazepines with some success. Aminophylline also appears to be a nonspecific antagonist of benzodiazepine depression but itself has side-effects.
Within 1–2 minutes of an intravenous dose, flumazenil permits awakening of a patient who may have become oversedated by benzodiazepines. If necessary, restoration to baseline levels of lucidity and alertness may be possible. Anesthesiologists may find this new drug useful in three clinical situations. First, flumazenil may be useful in the intraoperative period when a patient becomes confused, uncooperative, or combative after benzodiazepine admin-istration. Second, it may be infused at the conclusion of surgery, when the rapid return of consciousness was the desired objective but was not attained. Flumazenil might be useful either before or after extubation following upper airway surgery when bleeding or secretions might pose a significant problem in the patient who remains excessively somnolent. Third, either intraoperatively during moderate sedation or in the PACU, reversal of excessive midazolam sedation may allow a patient to safely tolerate the central nervous system depressant effects of other drugs that were administered concurrently.
The recommended dose of flumazenil is 0.2 mg given intravenously over 15 seconds. Its onset of action is 1–2 min-utes, and its peak action is 6–10 minutes. Incremental doses may be administered every minute, up to a total of 1 mg. Some recommend administration of the full 1 mg dose as a single bolus. Because flumazenil is a specific reversal agent with selectivity for benzodiazepine-induced seda-tion, it does not interfere with the analgesic state afforded by previously administered opioids. Its duration of action is highly variable, ranging from 20 minutes to 3 hours. Resedation may occur, and close patient surveillance is important. Resedation might occur in someone who received excessive doses of benzodiazepines, especially those agents with longer half-lives such as diazepam or lorazepam. If recognized, resedation can be safely managed by repeat administration of flumazenil at 20 minute inter-vals as required. Although excessive sedation and tranquility may be antagonized, flumazenil may not sufficiently reverse all the psychomotor and cognitive impairments induced by benzodiazepines. Thus, a false sense of security may be engendered. Furthermore, flumazenil may not entirely reverse respiratory depression caused by benzodiazepines. Mild side-effects reported in association with flumazenil administration include pain at the site of injection, dizziness, headache, precipitation of nausea and vomiting, acute anxi-ety, and disorientation. Seizures have also been precipitated in patients who have chronically used excessive amounts of benzodiazepines for anxiety or seizure control.
Midazolam has varying effects at different dosages. With small doses, it is anxiolytic. Increasing the dose administered increases the amount of sedation encountered. With still additional midazolam, the hypnotic effects of the agent become manifest. Careful titration of flumazenil may allow partial antagonism of excessive benzodiazepine effect.
When contemplating the use of any reversal agent in the setting of ambulatory surgery, it is important to remember that the duration of action of flumazenil, as well as nalox-one, is short-lived. Therefore, additional patient observation before discharge from the PACU is required whenever these agents have been administered.